Glucocorticoids have been widely employed in the treatment of immunologic disorders. Other steroid hormones, such as sex steroids, may also influence the clinical expression of immunologic disease. For, example, estrogens and their analogues have several known effects on the immune system. This group of sex hormones appears to increase the production of serum globulins, increase the phagocytic nature of mononuclear cells, increase the clearance of IgG-coated cells by splenic macrophages, and bind to and alter the functions of suppressor T-cells.
In autoimmune diseases such as thrombocytopenic purpurea (ITP) there is an increased clearance of platelets by macrophages in the spleen. ITP is believed to be caused by antiplatelet antibodies, which are frequently of the IgG class. These antibodies bind to the platelets forming IgG containing immune complexes. Levels of IgG on the platelet surface are generally elevated in patients with ITP; a change in the level of platelet-bound IgG in a given patient is often associated with a change in the platelet count with increases in bound IgG generally correlating with decreased platelet levels. The level of platelet-associated IgG, however, does not correlate uniformly with the platelet count in ITP. One explanation for this discrepancy may be differences in the rate or extent of clearance of platelets that is initiated by the adherence of IgG-coated platelets to surface Fc (IgG) receptors on tissue macrophages. For example, the rate of platelet clearance may be affected by processes that alter the capacity of macrophage Fc (IgG) receptors to recognize the IgG ligand.
In the spleen, IgG-containing immune complexes bind by the Fc region of IgG to macrophages at Fc receptor sites on the macrophage surface. The Fc portion of the immunoglobulin molecule (identified by papain cleavage) is believed to be responsible for biological activity other than antigen binding. The Fc portion is apparently responsible for complement fixation, transplacental transfer, binding to cells such as macrophages and granulocytes and the rate of synthesis and catabolism of the immunoglobulin molecule.
Expression of monocyte receptors for monomeric IgG varies widely among patients with ITP as compared with healthy donors. This variation in receptor expression may result from acquired changes in macrophage function or may reflect a more basic genetic disturbance. There is some evidence that the prevalence of ITP may be increased in several genetic subgroups. Abnormalities in the expression of function of Fc(IgG) receptors have been observed in association with certain HLA haplotypes. Moreover, both decreased numbers of C3b receptors (CR1) and uncommon CR1 allotypes have been noted in patients with systemic lupus erythematosus and members of their families. An increase in the number of Fc (IgG) receptors for monomeric IgG has been noted on the monocytes of patients with immune hemolytic anemia. These observations suggest that there may be a fundamental disturbance in the expression of monocyte or macrophage Fc (IgG) receptors in certain patients with ITP or other immunologic disorders.
An increase in the number of density of monocyte or macrophage Fc (IgG) receptors may result from the elaboration of such mediators as gamma interferon during an immune response or infection or the release of bacterial products. Alternatively, a decrease in the number of Fc (IgG) receptors available to bind IgG may result from their occupancy by circulating immune complexes that may be present in patients with ITP.
Autoimmune diseases are those diseases in which the body's mechanisms for distinguishing itself from foreign invaders has malfunctioned in some way. Typically, the body begins to make antibodies to certain parts of itself; these antibodies trigger the immune system which then destroys the tissue identified by the abnormal antibodies. Autoimmune diseases have varied focal points of attack. The autoimmune hemolytic anemias represent a group of disorders in which individuals produce antibodies to one or more of their own erythrocyte membrane antigens. Coating of erythrocytes by the abnormal antibodies is followed by their clearance from the circulation by splenic macrophages and subsequent destruction in the spleen. Representative diseases in this class are immune hemolytic anemia, immune thrombocytopenic purpura and autoimmune neutropenia. Another type of autoimmune disease is the type represented by systemic lupus erythematosus and rheumatoid arthritis. In these diseases, chronic inflammation is present in the joints, tendons, kidneys, lung, heart and other organs. In rheumatoid arthritis, for example, breakdown of joint cartilage into the synovial fluid of the joint is present in later stages of the disease. In systemic lupus erythematosus, however, cartilage or bone degradation is not usually found. Systemic lupus erythematosus and rheumatoid arthritis are often present in conjunction with other types of autoimmune disease. In systemic lupus erythematosus and rheumatoid arthritis, tissue destruction is associated with the presence of IgG-containing complexes in the circulation. It is believed that recognition of these complexes in tissues by cells having Fc receptors initiates or increases tissue destruction by macrophages and possibly other cells such as polymorphonuclear leukocytes in these tissues.
Diseases characterized by interactions of IgG containing immune complexes with macrophage Fc receptors, such as autoimmune diseases, are often chronic and cause much suffering to victims. Treatments currently available have serious side effects.
Corticosteriods inhibit clearance of IgG-coated erythrocytes by modulating splenic macrophage F.sub.c (IgG) receptor activity. They have been used in treating autoimmune disorders such as immune thrombocytopenic purpura and systemic lupus erythematosus. However, corticosteroids have undesirable side effects such as exacerbation of diabetes, hypertension, electrolyte imbalance, increased appetite and weight gain, moonlike faces, osteoporosis, myopathy and increased susceptibility to infection. The severity of these side-effects is related to both the duration and dosage of therapy.
Progesterone has been observed to inhibit splenic macrophage clearance of IgG-coated erythrocytes by fifty percent. Nettl et al, Blood 64: Suppl 1:8 A (Abstract) (1984). However, progesterone is a progestational agent, and exerts substantial sex-organ hormonal effects, making its use in treatment less than optimal.
The autoimmune disease chronic immune thrombocytopenic purpura has been treated with danazol, an antigonadotropic drug. Ahn et al, N. Engl. J. Med. 308: 1396-1399 (1983); Schreiber et al, N. Engl. J. Med. 316: 503-508 (Feb. 26, 1987). Danazol is a synthetic analogue of androgenic steroids and progesterone. As an androgen, danazol can cause masculinization. Moreover, use of this drug in treating systemic lupus erythematosus has been associated with a high incidence of side-effects such as a rise in hepatic enzymes, skin rash, weight gain, acne and myalgia. Dougados et al, Arthritis Rheum. (Suppl.) 28: 246 (1985); Jungers et al, Arthritis Rheum. 28: 1234-1250 (1985).
The synthetic hydroxyprogesterone derivative, cyproterone acetate has been used in treating female patients having moderately active systemic lupus erythematosus. Jungers et al, supra. Cyproterone acetate is an antigonadotropic agent possessing peripheral antiandrogenic effects. As an antigonadotropic agent, it affords contraception in females. Despite achieving some success in treating systemic lupus erythematosus, it is likely that cyproterone acetate has progestational activity, making it undesirable in treatment. Moreover, it has been reported that antigonadotropic drugs such a cyproterone acetate and danazol should not be used in male systemic lupus erythematosus patients. Jungers et al, supra. In males, the antigonadotropic effect of cyproterone acetate induces a marked decrease in plasma testosterone concentration. In addition, cyproterone acetate acts as an antiandrogen in displacing 5-dihydrotestosterone from a specific receptor in the prostate. According to Jungers et al. supra, administration of cyproterone acetate in male systemic lupus erythematosus patients should induce a marked fall in plasma testosterone level which could potentially provoke an exacerbation of clinically active systemic lupus. Danazol was reported to unmask latent systemic lupus erythematosus in a male patient treated for angioneurotic edema. Fretwell et al, J. Allergy Clin. Immunol 69: 306-310 (1982).
The estrogen antagonist/agonist tamoxifen, another candidate for use in treating autoimmune disease, has been observed to enhance the clearance of IgG-coated cells, but to a lesser extent than estradiol alone. Friedman et al., J. Clin. Invest. 75:162-167 (1985).
The use of progesterone in inhibiting immune clearance of antibody-coated cells from the circulation, and therefore its potential use in treating disorders such as systemic lupus erythematosus, immune hemolytic anemia and immune thrombocytopenic purpura, is unattractive because of progesterone's sex-organ hormonal effects. There is a need, therefore, for treatments for diseases characterized by interactions of IgG-containing immune complexes with macrophage Fc receptors which have the immune clearance modulating activity of progesterone without the progestational sex-organ hormonal effects of progesterone and the side-effects of other treatments. Accordingly, it is an object of the invention to provide methods of treating these diseases without the undesired effects discussed above and to provide drugs and drug compositions for such uses.